Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

• MeSH
• Child MeSH
• Dyskeratosis Congenita * genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Telomere-Binding Proteins * genetics   metabolism   MeSH
• Shelterin Complex MeSH
• Telomere * genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

• MeSH
• Autoimmune Pancreatitis * drug therapy   diagnosis   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Steroids therapeutic use   administration & dosage   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH

The field of cardiac pacing has changed rapidly in the last several years. Since the initial description of His bundle pacing targeting the conduction system, recent advances in pacing the left bundle branch and its fascicles have evolved. The field and investigators' knowledge of conduction system pacing including relevant anatomy and physiology has advanced significantly. The aim of this review is to provide a comprehensive update on recent advances in conduction system pacing.

• MeSH
• Bundle-Branch Block therapy   MeSH
• Electrocardiography MeSH
• Bundle of His * MeSH
• Humans MeSH
• Cardiac Conduction System Disease therapy   MeSH
• Heart Conduction System MeSH
• Cardiac Resynchronization Therapy * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The development of an ideal vascular prosthesis represents an important challenge in terms of the treatment of cardiovascular diseases with respect to which new materials are being considered that have produced promising results following testing in animal models. This study focuses on nanofibrous polycaprolactone-based grafts assessed by means of histological techniques 10 days and 6 months following suturing as a replacement for the rat aorta. A novel stereological approach for the assessment of cellular distribution within the graft thickness was developed. The cellularization of the thickness of the graft was found to be homogeneous after 10 days and to have changed after 6 months, at which time the majority of cells was discovered in the inner layer where the regeneration of the vessel wall was found to have occurred. Six months following implantation, the endothelialization of the graft lumen was complete, and no vasa vasorum were found to be present. Newly formed tissue resembling native elastic arteries with concentric layers composed of smooth muscle cells, collagen, and elastin was found in the implanted polycaprolactone-based grafts. Moreover, the inner layer of the graft was seen to have developed structural similarities to the regular aortic wall. The grafts appeared to be well tolerated, and no severe adverse reaction was recorded with the exception of one case of cartilaginous metaplasia close to the junctional suture.

• Publication type
• Journal Article MeSH

BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC. METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided. RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively). CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

• MeSH
• Cohort Studies MeSH
• Humans MeSH
• Breast Neoplasms * genetics   radiotherapy   drug therapy   MeSH
• Prospective Studies MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• Publication type
• Overall MeSH

• MeSH
• Emergencies MeSH
• Critical Care MeSH
• Wounds and Injuries MeSH
• Emergency Treatment MeSH
• Publication type
• Atlas MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• urgentní lékařství
• NML Publication type
• kolektivní monografie

Text je věnován životu a dílu kněze, pedagoga a spisovatele Hieronyma Antona Jarische (1818–1890). Vyzdvihuje důležité momenty jeho života spjaté se vzděláváním ne- slyšících a zejména jeho propojení s pražským ústavem pro hluchoněmé, Václavem Frostem a znakovým jazykem užívaným na území Čech, respektive Rakouského císařství. Největší pozornost je věnována jeho dílu Methode für den Unterricht der Taub-Stummen in der Laut-Sprache im Rechnen und in der Religion (1851), jehož součástí je i obrázkový slovník znaků, které mohou být částečně považovány za historicky první doložitelné obrázky znaků českého znakového jazyka.

The text focuses on the life and work of the priest, teacher and writer Hieronymus Anton Jarisch (1818-1890). It highlights important moments in his life connected with the education of the deaf and especially his connection with the Prague Institute for the Deaf and Dumb, Václav Frost and the sign language used in Bohemia and the Austrian Empire. The emphasis is placed on his book Methode für den Unterricht der Taub-Stummen in der Laut-Sprache im Rechnen und in der Religion (1851), which includes a picture dictionary of signs that can be partly regarded as the first historically documentable pictures of Czech Sign Language signs.

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

• MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Heterozygote MeSH
• Humans MeSH
• Mutation MeSH
• Breast Neoplasms * diagnosis   epidemiology   genetics   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

• MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Cohort Studies MeSH
• Contraceptives, Oral administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Ovarian Neoplasms epidemiology   genetics   prevention & control   MeSH
• Follow-Up Studies MeSH
• Proportional Hazards Models MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Retrospective Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH